Pharmacological inhibition of arginine and lysine methyltransferases induces nuclear abnormalities and suppresses angiogenesis in human endothelial cells.

Abstract

Posttranslational modifications of histone tails can alter chromatin structure and regulate gene transcription. While recent studies implicate the lysine/arginine protein methyltransferases in the regulation of genes for endothelial metabolism, the role of AMI-1 and AMI-5 compounds in angiogenesis remains unknown. Here, we show that global inhibition of arginine and lysine histone methyltransferases (HMTs) by AMI-5 induced an angiostatic profile in human microvascular endothelial cells and human umbilical vein endothelial cells. Based on FACS analysis, we found that inhibition of HMTs significantly affects proliferation of endothelial cells, by suppressing cell cycle progression in the G0/G1 phase. Immunofluorescent studies of the endothelial cells replication pattern by 5-ethynyl-2'-deoxyuridine incorporation disclosed that AMI-5, and the arginine methyltransferase inhibitor AMI-1, induced heterochromatin formation and a number of nuclear abnormalities, such as formation of micronuclei (MNs) and nucleoplasmic bridges (NPBs), which are markers of chromosomal instability. In addition to the modification of the cell cycle machinery in response to AMIs treatment, also endothelial cells migration and capillary-like tube formation processes were significantly inhibited, implicating a stimulatory role of HMTs in angiogenesis.

• Authors: Aneta Balcerczyk, Dorota Rybaczek, Martyna Wojtala, Luciano Pirola, Jun Okabe, Assam El-Osta
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 121 Pg. 18-32 (Dec 01 2016) ISSN: 1873-2968 [Electronic] England
• PMID: 27659811 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 2-(2,4,5,7-tetrabromo-3-oxido-6-oxoxanthen-9-yl)benzoate
• 7,7'-carbonylbis(azanediyl) bis(4-hydroxynaphthalene-2-sulfonic acid
• Angiogenesis Inhibitors
• Benzoates
• Heterochromatin
• Naphthalenesulfonates
• Xanthenes
• Urea
• Protein-Arginine N-Methyltransferases
• Histone-Lysine N-Methyltransferase

Topics

• Angiogenesis Inhibitors (pharmacology)
• Benzoates (pharmacology)
• Cell Cycle (drug effects)
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Endothelial Cells (drug effects, enzymology)
• Heterochromatin (drug effects, pathology)
• Histone-Lysine N-Methyltransferase (antagonists & inhibitors)
• Humans
• Micronuclei, Chromosome-Defective (drug effects)
• Naphthalenesulfonates (pharmacology)
• Neovascularization, Pathologic (enzymology, prevention & control)
• Protein-Arginine N-Methyltransferases (antagonists & inhibitors)
• Urea (analogs & derivatives, pharmacology)
• Xanthenes (pharmacology)